Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects.
Purpose: Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 m...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 69; no. 3; pp. 523 - 533 |
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| Autores principales: | , , , , |
| Formato: | research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Springer Nature
Mar2013
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104314265&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104314265 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Mar2013 vid: 69 iid: 3 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 104314265 85456589 10.1007/s00228-012-1403-6 NLM22990330 104314265 ppf: 523 ppct: 10 formats: fmt: @attributes: type: P tig: atl: Pharmacokinetic interactions of almorexant with midazolam and simvastatin, two CYP3A4 model substrates, in healthy male subjects. aug: au: Hoch, Matthias Hoever, Petra Alessi, Federica Theodor, Rudolf Dingemanse, Jasper affil: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16 4123 Allschwil Switzerland sug: subj: Midazolam Administration and Dosage Simvastatin Administration and Dosage Hypnotics and Sedatives Administration and Dosage Drug Interactions Hypnotics and Sedatives Pharmacokinetics Simvastatin Pharmacokinetics Midazolam Pharmacokinetics Human Male Randomized Controlled Trials Crossover Design Confidence Intervals Oxidoreductases Drug Effects Adult Middle Age Data Analysis Software Descriptive Statistics Germany Analysis of Variance Wilcoxon Signed Rank Test Funding Source Adult: 19-44 years Middle Aged: 45-64 years Male ab: Purpose: Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates. Methods: Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9. Results: Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4-5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0-1.4], 1.4-fold (90 % CI 1.2-1.6), and 1.3-fold (90 % CI 1.2-1.4) in the maximum plasma concentration (C), area under the concentration-time curve from time 0 to infinity (AUC), and terminal half-life (t), respectively, of midazolam; the time to peak plasma concentration (t) was unchanged. Whereas C and t were not influenced by almorexant, the AUC of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1-1.4) and the t by 1.3-fold (90 % CI 1.0-1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0-3.7) and 3.4-fold (90 % CI 2.6-4.4) in C and AUC, respectively, for simvastatin; the t and t were unchanged. The C and AUC of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3-3.5 and 2.2-3.5, respectively; the t increased by 2 h and the t was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant. Conclusions: Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level. pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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